Last week I wrote about reactive hypoglycemia, a form of blood sugar dysregulation in which blood sugar plummets after a meal, primarily in response to the overconsumption of refined carbohydrates and sugars. However, these foods are not the only cause. One other primary cause of hypoglycemia is dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis. This week we’ll continue talking about blood sugar and go into more detail about the relationship between the HPA axis and hypoglycemia.

Normally the adrenal glands kick into action in response to low blood sugar, as in the case of a skipped meal. When we miss a meal and we become hypoglycemic, the adrenal glands release stress hormones like cortisol that raise blood sugar. In this role, the adrenals can be thought of as an “emergency backup.” They also play a central role in the “fight or flight” sympathetic nervous system response. The adrenal glands are part of a larger picture neuroendocrine system known as the HPA axis, which we will explore in more detail shortly.

Over time, downregulation of the HPA axis can lead to a vicious cycle of blood sugar imbalance. Long-term recurrence of hypoglycemic episodes puts a lot of strain on the adrenal glands, which over time become unable to raise blood sugar through the release of cortisol, a primary stress hormone. This can become a vicious cycle in which the adrenal glands are unable to raise blood sugar, resulting in hypoglycemic symptoms such as dizziness, shakiness, perspiration and a short temper, which is commonly referred to as being “hangry.”

To learn about the physiology that underlies this phenomenon, commonly referred to as “adrenal fatigue” or “adrenal insufficiency,” keep reading! I’ll cover how to support the adrenal glands and rebalance the HPA axis in order to get out of this vicious cycle!

The HPA axis and its role in the stress response

The HPA axis is a neuroendocrine system that leaps into action in response to perceived stress. The hypothalamus initiates the stress response cascade by releasing corticotropin-releasing hormone (CRH). CRH binds to receptors on the anterior pituitary gland, which in turn stimulates the pituitary to release adrenocorticotropic hormone (ACTH). Receptors on the zona fasciculata region of the adrenal cortex bind ACTH and stimulate the adrenal release of cortisol into the bloodstream.​

The hypothalamus monitors blood concentrations of cortisol, and when levels reach an adequate level the hypothalmus concludes that the stress has been controlled and dealt with. Elevated blood cortisol levels signal the hypothalamus to stop releasing CRH through a negative feedback loop. In response, the pituitary stops releasing ACTH, which in turn stops stimulating the adrenal release of cortisol and homeostasis is achieved.

Not just the adrenal glands are implicated

The adrenal glands themselves are sometimes viewed as the culprit and we hear about “adrenal fatigue” as an explanation for the body’s inability to release sufficient cortisol to raise blood sugar. Although the adrenals are an important component of the body’s stress response, we must also consider the hypothalamus and pituitary to understand the bigger picture. Keep reading to learn how these “upstream” glands that govern adrenal function factor into the larger picture.

What does the body consider to be stressful?

Before we get to the details of the HPA axis, let’s talk about stress, since stress is a primary activator of the HPA axis.

Stress can come from many sources. From an evolutionary point of view, stressors were generally situations that could be life threatening, such as the presence of a lethal predator that one must either incapacitate or run away from, hence the term “fight or flight.” Other stressors include situations in which a child or another member of the tribe is in danger, as in the case of a child falling into a rushing river. The stress response kicks into action to give us a temporary burst of superhuman strength and energy to outrun the bear or rescue the helpless child from the raging rapids.

Today, we have largely removed ourselves from the food chain and live pretty safe lives in comparison to much of our evolutionary history. However, we deal with different sources of stress today. Stress today tends to be more chronic. We’ll review a few common contemporary stressors here:

• Watching a suspenseful TV show or movie
• Job stress, such as an angry boss or an upset customer
• Fear about public speaking at an upcoming meeting
• Being involved in a car accident or a near-collision
• Inflammation
• Excessive exercise, especially sustained exercise like marathon running
• Hypoglycemia – this is a big one that we’ll return to shortly!

Although some of these stressors may sound relatively trivial, they stimulate the same physiological stress response in the body as being chased by a bear. Some other, more serious forms of chronic stress can result from:

• Sexual assault and other forms of trauma
• PTSD, as in the case of war veterans
• Being a caregiver for a chronically ill family member
• Emotional stress resulting from depression or abuse

The effects of chronic stress

In contrast to occasional acute stress such as a bear that we must outrun to survive, much of today’s stress is chronic. Chronic stress, such as an overbearing or unreasonable boss that stresses us out at the office all day long results in frequent stimulation of the HPA axis and elevated cortisol levels. Over time, the stress response becomes blunted as the adrenal glands become less responsive to ACTH. As a result, cortisol levels decline, which we see in our office when performing DUTCH cortisol urine testing.

We like the DUTCH test because it assesses levels of cortisol four times over the course of the day. Normally, cortisol levels are highest in the morning as this hormone helps to stimulate us to wake up. Cortisol levels then decline over the course of the day and typically reach their lowest levels in the evening and night when we become tired and go back to sleep. However, what we see in our clinic with adrenal insufficiency is consistently low levels of cortisol over the course of the day.

The difference between chronic and acute stress

A helpful analogy to understand the difference between chronic and acute stress and how the HPA axis is intended to function is to observe a wild animal such as a deer. Picture a deer in a meadow, peacefully munching on grass. Suddenly, a wolf appears on the horizon and begins running toward the deer at full speed, hoping to turn Bambi into a nice lunch for himself. In a split second, the deer’s HPA axis shifts the nervous system into “fight or flight” and its adrenal glands secrete cortisol into the bloodstream.

Bambi takes off at full speed, and thankfully is able to outrun and elude the wolf, which gives up and goes after other, easier prey. After determining that the threat has passed, what does the deer do? He settles down in the shade and takes a nap. This period of rest allows the HPA axis to reset and recharge. This component of rest and rejuvenation is crucial, and is much different than what happens in cases of chronic stress.

Chronic stress paints a much different picture. Picture Bill, a sales associate who works in a busy office. A stressful morning meeting in which Bill’s boss grills him for numbers that aren’t up to par initiates a stress response and sends cortisol into Bill’s bloodstream. After the meeting, Bill grabs a cup of coffee to give him an energy boost. The coffee stimulates the release of more cortisol, and then Bill skips lunch to catch up on paperwork, which results in even more stress and cortisol release. Then, Bill spends his afternoon “putting out fires” and finishes out the rest of his day just as stressed as he started.

Unlike the deer in the previous example, Bill doesn’t get a chance to rest and instead stays in “fight of flight” mode all day. Over a period of several weeks or months, Bill’s ability to respond appropriately to stress is compromised, resulting in downregulation of the HPA axis. With this understanding of the difference between acute and chronic stress in mind, we’ll talk next about the vicious cycle of HPA downregulation and hypoglycemia.

The hypoglycemia connection

As I alluded to earlier, hypoglycemia can be both a cause of, and result of HPA axis dysregulation. Hypoglycemia that results from frequently skipping meals puts strain on the adrenal glands, which respond by secreting cortisol. Elevated cortisol levels stimulate gluconeogenesis, a process by which glucose is synthesized from pyruvate (1). Gluconeogenesis primarily takes place in the liver and kidneys and is one primary way the body is able to raise blood sugar levels.

But when the HPA axis becomes downregulated, the adrenal glands become resistant to the stimulatory effects off ACTH. Consequently, they do not secrete as much cortisol. This imbalance is commonly referred to “adrenal fatigue” or “adrenal insufficiency,” but as I described earlier the problem involves the whole HPA axis and not just the adrenals.

Whatever terminology is used to describe this phenomenon, the end result is that the adrenal glands no longer secrete adequate amounts of cortisol to raise blood sugar and the ability to resolve hypoglycemia by activating gluconeogenesis is compromised.

Testing for HPA dysregulation

An important first step in treating hypoglycemia that is related HPA dysregulation is establishing a baseline cortisol profile through a DUTCH adrenal dried urine test. This is our preferred test because it evaluates cortisol levels four times over the course of a 24 hour period. The DUTCH test is preferable to single collection cortisol tests that only measure total cortisol for a 24 hour period because total cortisol for the day doesn’t provide as clear of a picture. For example, low levels of cortisol throughout much of the day could be hidden by a cortisol spike that pushes total cortisol for the period into normal, or even elevated ranges.